Apoptosis of neurons may be induced in normal physiological functions such as the Neural development or in pathological processes such as diseases. During the developmental process of neurons, excess neurons are removed through apoptosis in order for optimal, precise connection between presynapse and postsynapse (Neuron, 40:401-413(2003); Neuron, 20:633-647(1998)). A wide range of apoptosis of neurons is observed in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease, a stroke and external injuries. The direct cause of these diseases has not been found yet, however, this is associated with apoptosis and the apoptosis is affected by various factors such as oxidative stress, dysregulation of calcium homeostasis, dysfunction of mitochondria, an increase in the generation of reactive oxygen species, excitotoxicity, caspase activation, and trophic deprivation (Nature Reviews Molecular Cell Biology, 1:120-130(2000), Neurotoxicology and Teratology, 24:675-682(2002)).
In the case of Parkinson's disease, it is reported that the dysfunction of mitochondria increases the secretion of calcium and the generation of reactive oxygen species, thereby inducing oxidative stress to decrease the activity of antioxidative systems. In addition, there is a report about association between excitotoxicity by glutamate and Parkinson's disease (Neurotoxicology and Teratology, 24:675-682(2002)).
In the case of Alzheimer's disease, it is reported that the apoptosis of neurons is associated with oxidative stress, dysregulation of ion homeostasis, growth factor deprivation, accumulation of amyloid Aβ, metabolic impairment, dysfunction of mitochondria, DNA damage, and protein aggregation (Nat. Rev. Neurosci., 7:278-294(2006); Cerebellum, 2:270-278(2003)).
Currently, various types of neuroprotective agents used for protecting neurons from apoptosis induced by various mechanisms are proposed (Neurotoxicology and Teratology, 24:675-682(2002)). Examples of the neuroprotective agents include antioxidants, ion chealators, free radical scavengers, neurotrophic factors, excitatory amino acid antagonists, bioenergic supplements, immunosuppressants, and formulations preventing aggregation or accumulation of protein. However, medicines that effectively inhibit apoptosis of neurons or neurodegeneration are not commercially available yet, and thus there is still a need to develop a pharmaceutical composition for inhibiting apoptosis of neurons or neurodegeneration.